Reference Detail

Ref Type Journal Article
PMID (21926964)
Authors Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, Sattler M
Title Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms.
Journal Leukemia
Vol 26
Issue 4
Date 2012 Apr
URL
Abstract Text The transforming JAK2V617F kinase is frequently associated with myeloproliferative neoplasms and thought to be instrumental for the overproduction of myeloid lineage cells. Several small molecule drugs targeting JAK2 are currently in clinical development for treatment in these diseases. We performed a high-throughput in vitro screen to identify point mutations in JAK2V617F that would be predicted to have potential clinical relevance and associated with drug resistance to the JAK2 inhibitor ruxolitinib (INCB018424). Seven libraries of mutagenized JAK2V617F cDNA were screened to specifically identify mutations in the predicted drug-binding region that would confer resistance to ruxolitinib, using a BaF3 cell-based assay. We identified five different non-synonymous point mutations that conferred drug resistance. Cells containing mutations had a 9- to 33-fold higher EC(50) for ruxolitinib compared with native JAK2V617F. Our results further indicated that these mutations also conferred cross-resistance to all JAK2 kinase inhibitors tested, including AZD1480, TG101348, lestaurtinib (CEP-701) and CYT-387. Surprisingly, introduction of the 'gatekeeper' mutation (M929I) in JAK2V617F affected only ruxolitinib sensitivity (fourfold increase in EC(50)). These results suggest that JAK2 inhibitors currently in clinical trials may be prone to resistance as a result of point mutations and caution should be exercised when administering these drugs.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
E985K missense unknown JAK2 E985K lies within the protein kinase domain 2 of the Jak2 protein (UniProt.org). E985K has been described as a secondary drug resistance mutation (PMID: 21926964), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2019). Y
I960V missense unknown JAK2 I960V lies within the protein kinase domain 2 of the Jak2 protein (UniProt.org). I960V has been described as a secondary drug resistance mutation in the context of JAK2 V617F (PMID: 23009939, PMID: 21926964), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2019). Y
M929I missense gain of function - predicted JAK2 M929I is a gatekeeper mutation that lies within the protein kinase 2 domain of the Jak2 protein (PMID: 22916261, PMID: 23823659). M929I is predicted to confer a gain of function to the Jak2 protein as demonstrated by increased Jak2 and Stat5 phosphorylation (PMID: 22916261), and has also been described as a secondary drug resistance mutation in the context of other Jak2 activating mutations (PMID: 22916261, PMID: 23823659, PMID: 21926964). Y
R938L missense unknown JAK2 R938L lies within the protein kinase domain 2 of the Jak2 protein (UniProt.org). R938L has been demonstrated to occur as a secondary drug resistance mutation (PMID: 21926964), but has not been biochemically characterized and therefore, its effect on Jak2 protein function is unknown (PubMed, Apr 2019). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
JAK2 V617F JAK2 I960V hematologic cancer resistant Momelotinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Momelotinib in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 R938L hematologic cancer resistant Momelotinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to Momelotinib (CYT387) in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 I960V hematologic cancer resistant SAR302503 Preclinical - Cell culture Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Fedratinib (SAR302503) in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 I960V hematologic cancer resistant AZD1480 Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to AZD1480 in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 R938L hematologic cancer resistant SAR302503 Preclinical - Cell culture Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to fedratinib (SAR302503) in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 M929I hematologic cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 M929I double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 R938L hematologic cancer resistant Lestaurtinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to lestauranib in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 I960V hematologic cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 R938L hematologic cancer resistant AZD1480 Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to AZD1480 in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 E985K hematologic cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 E985K double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 R938L hematologic cancer resistant Ruxolitinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 R938L double mutation demonstrated resistance to Jakafi (Ruxolitinib) in culture (PMID: 21926964). 21926964
JAK2 V617F JAK2 I960V hematologic cancer resistant Lestaurtinib Preclinical Actionable In a preclinical study, immune cells expressing the JAK2 V617F and JAK2 I960V double mutation demonstrated resistance to Lestauranib in culture (PMID: 21926964). 21926964